Diet and Lifestyle in the Prevention of ColorectalCancer: An Overview

Moshe Shike, MD

Numerous lifestyle factors have been implicated incolorectal carcinogenesis. These include diet, inad-equate physical activity, obesity, alcohol consump-tion, and smoking. Epidemiologic studies, animal ex-periments, and randomized clinical trials have shownthat dietary factors can influence all stages of colo-rectal carcinogenesis, from cell proliferation totransformation to cancer. Defining the precise role ofdiet and other lifestyle factors in colorectal carcino-genesis may require the elucidation of genetic sus-ceptibility and genetic–environmental interactions.Despite the preoccupation with nutrition by the pub-lic and the media in the United States, trends in foodconsumption have not been favorable. The averageU.S. diet is still too high in calories and fat and toolow in fiber, cereals, fruits, and vegetables. Dietarymodifications along with secondary preventionmeasures may have a major impact on reducing themortality from colorectal cancer. Am J Med. 1999;106(1A):11S–15S. © 1999 by Excerpta Medica, Inc.

The majority of colorectal cancers are considered“sporadic” in the sense that there is no clear familyhistory to suggest an inherited mutation that

would explain the occurrence of the cancer. In such can-cers, environmental and biologic factors may play a cru-cial etiologic role. These factors include diet, inadequatephysical activity, obesity, and associated diseases such asulcerative colitis. It has been suggested that environmen-tal factors, particularly the diet, play a central etiologicrole in colon cancer.1 Epidemiologic studies and experi-ments in animals and humans have shown that dietaryfactors can influence all stages of carcinogenesis, includ-ing cell proliferation, adenoma formation, and transfor-mation to cancer. Defining the precise role of dietary andother lifestyle factors in colon carcinogenesis may requirethe elucidation of genetic predisposition and genetic– en-vironmental interactions. Lack of consideration of inher-ited susceptibility to the effects of dietary factors may ex-plain some of the inconsistencies in the epidemiology lit-erature regarding the association between diet and therisk of colorectal cancer.

Despite wide interest in nutrition, trends in food con-sumption in the United States over the past three decadeshave not been favorable. The incidence of obesity—a pos-sible risk factor for colorectal cancer as well as for otherdiseases—is on the rise. Although there has been a slightreduction in the percentage of calories from fat in the U.S.diet, the intake of fiber, whole grains, fruits, and vegeta-bles remains low.

DIET

Numerous dietary factors, including excess calories, highfat content, and low intake of fiber, fruits and vegetables,cereals, calcium, and vitamins, have been implicated incolon carcinogenesis.2–5 The literature on diet and colo-rectal cancer has been reviewed in recent publications.3,5

Studies of migrants are of particular significance in un-derscoring the role of the diet in colon carcinogenesis.The fact that individuals from countries with a low inci-dence of colorectal cancer acquire an increased risk of thedisease when they move to countries with a high inci-dence strongly suggests that environmental factors, mostlikely diet, modify the risk.6,7 Various mechanisms havebeen proposed to explain the effects of dietary compo-nents on colon carcinogenesis. These include modifica-tion of the putative damaging effects of bile acids on co-lonic mucosa, direct damage to DNA by products of fat

From the Department of Medicine, GI-Nutrition Service, MemorialSloan-Kettering Cancer Center, New York, New York.

Requests for reprints should be addressed to Moshe Shike, MD, Can-cer Prevention and Wellness Program, Memorial Sloan-Kettering Can-cer Center, 1275 York Avenue S-524, New York, New York 10021.

© 1999 by Excerpta Medica, Inc. 0002-9343/99/$19.00 11SAll rights reserved. PII S0002-9343(99)00340-4

peroxidation, changes in colonic bacterial metabolism,and decreased protection due to inadequate antioxi-dants.5

Many studies have addressed the role of specific dietaryfactors in colorectal carcinogenesis. Low-fat diets, both inlaboratory animal studies8 and in epidemiologic observa-tions, have been found to exert a protective effect.9 –11

Some studies suggest that specific dietary fat sources suchas red meat9 and vegetable fat12 are to blame for colorectalcancer. High total caloric intake has also been implicatedas a risk factor. Calorie-restricted diets in animals are as-sociated with a reduced rate of various tumors, includingchemically induced colorectal cancer.13 A case-controlstudy revealed that subjects with colorectal cancer hadhigher caloric intakes than controls during the 5 yearspreceding the diagnosis of cancer.14

The hypothesis that dietary fiber can protect againstcolorectal cancer originated from observations that Afri-cans eating high-fiber diets have a low rate of death fromcolorectal cancer.15 Some epidemiologic studies supportthe hypothesis,16 –18 but others do not.19 The inconsis-tency may be due to the fact that fiber is not a specificchemical entity and that various fibers can affect the co-lonic mucosa in different ways. Thus, in rats, wheatbran,20 but not pectin,21 protects against chemically in-duced colorectal cancer. In a double-blind, controlledstudy, neither wheat bran nor calcium had an effect oncolonic mucosal cell proliferation (measured by 3H-thy-midine labeling).22 However, large-dose fiber reduced fe-cal bile acid concentration and excretion.

Further support for the role of diet in the developmentof colorectal cancer comes from the Australian Polyp Pre-vention Project, a randomized study in which a low-fatdiet supplemented with wheat bran was found to be as-sociated with a significant reduction in the recurrencerate of large adenomas (defined as .1 cm).23 This findingmay also indicate that diet affects primarily the growthrate of adenomas rather than the formation of new, smalladenomas.

Role of Micronutrients and SupplementsThe role of calcium in protecting against colorectal can-cer has been investigated in laboratory animals,24 epide-miologic studies,25–27 and human intervention stud-ies.28,29 A 19-year cohort case-control study found an in-verse correlation between calcium intake and theincidence of colorectal cancer.26 However, another study,of 2,000 Hawaiian-Japanese men, found no correlationbetween calcium intake and colorectal cancer inci-dence.27 Results of intervention studies in humans havealso been inconsistent. In a study of subjects at high riskfor colorectal cancer because of family history, the ele-vated proliferation indexes of the colonic mucosa de-creased by 50% and shifted to a quiescent pattern aftercalcium supplementation for 2–3 months.28 These results

were not, however, confirmed in a randomized, placebo-controlled study involving 333 patients at high risk forcolorectal neoplasia; calcium supplementation for 1 yearhad no effect on rectal mucosal proliferation.29

A variety of antioxidants, including beta carotene, vi-tamins E and C, and selenium, have been proposed ascancer prevention agents.5 In a multifactorial random-ized study, neither beta carotene nor the combination ofvitamins E and C reduced the rate of adenoma recur-rence.30 Low blood levels of selenium have been associ-ated with an increased risk of cancer in several organs.31 Arandomized study designed to examine the effects of se-lenium supplementation on skin cancer found inciden-tally that the group that received selenium supplementa-tion had a 40% decrease in colorectal cancer.32

Effect on Epithelial HyperproliferationDietary factors appear to play a role in each stage of thecontinuum from normal colonic mucosa to colorectalcancer, beginning with modification of the colonic mi-lieu, induction of hyperproliferation, and formation ofaberrant crypt foci (Figure 1). Support for this conceptcomes from experimental studies in animals and hu-mans.22,28,29,33 In a study in humans, the amount of di-etary fat modified the colonic cells’ proliferative index-es.33 In another study, calcium supplementation given topatients with an inherited predisposition to colorectalcancer reduced the high rate of cell proliferation of thecolonic mucosa.28 It is not clear whether these diet-in-duced modifications of the indexes of proliferation of thecolonic mucosa persist for periods longer than those inthe experiments and whether they indeed affect laterstages of carcinogenesis.

Effect on Adenoma FormationNumerous epidemiologic studies show that people whoconsume high-fat, low-fiber diets are at greater risk ofadenoma formation than those who eat low-fat, high-fiber diets.34

Dietary and digestive factors may be necessary to in-duce the carcinogenic process, even when a strong geneticpredisposition already exists. Evidence for such a conceptcomes from a recent study in mice.35 The mutation in theadenomatous polyposis coli (APC) gene is considered avery early, and possibly the earliest, change in the geneticmakeup of colonic mucosal cells that leads to colorectalcancer. In a recently published study,35 investigators ex-cluded a segment of the colon from the fecal stream inmice with a germ-line mutation of the APC gene. As ex-pected, many adenomas developed in the colon exposedto the fecal stream, but none developed in the excludedsegment. This finding suggests an interaction between thegene mutation and a factor or factors within the colonlumen (dietary components, digestive secretions, or mi-croflora) without which adenoma formation cannot pro-ceed. This finding also illustrates the concept that genetic-

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environmental interaction is a necessary condition forthe neoplastic process.

PHYSICAL ACTIVITY AND OBESITY

In numerous epidemiologic studies, inadequate physicalactivity appears to be a risk factor for colorectal cancer. Inone longitudinal study of 17,000 people followed for 25years, individuals who expended .2,500 kcal/week inadded physical activity had half the risk of developingcolorectal cancer of those who expended ,1,000 kcal/week.36 Similar studies, using adenomas or adenomasand carcinomas as endpoints, have suggested the impor-tance of physical activity as a factor in reducing the risk ofcolorectal cancer.37,38

Obesity appears to be a risk factor for colorectal cancer,although the data are inconsistent.39 In a longitudinalobservational study, subjects who had a high body massindex (.75th percentile) during adolescence were foundduring adulthood to be at a substantially increased riskfor colorectal cancer.40 In another epidemiologic survey,obesity was found to be a risk factor for the developmentof adenomas.41 However, other studies do not supportthis finding.39 It has been suggested that increased bodymass index is associated with larger adenomas. This hy-pothesis is, however, not well substantiated.37

It is not clear whether obesity and inadequate physicalactivity each exerts an independent effect or together ex-ert an interdependent effect on the risk of colorectal can-cer, since inadequate physical activity often results in

weight gain. In a cohort study involving 47,727 partici-pants, body mass index independent of physical activitywas closely associated with the risk of colorectal cancer.38

CIGARETTE SMOKING AND ALCOHOLCONSUMPTION

The association between cigarette smoking and the risk ofcolorectal cancer has been examined in a number of stud-ies. In a French colonoscopy study, the incidence of co-lonic adenoma was twice as high among smokers asamong nonsmokers.42 Some studies using sigmoidos-copy reached the same conclusion,43,44 but numerousother studies and reviews of the literature have not con-firmed an association between smoking and colorectalcancer.45,46

Excessive alcohol consumption has been reported to bea risk factor for colorectal adenomas and cancer.47,48

Some studies found an association between beer drinkingand cancer and adenomas, but no association was foundwith either wine or spirits.49,50 The results of these epide-miologic studies must be interpreted with great caution,since most did not consider important variables such asfamily history and diet.

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Figure 1. The transformation from normal colorectal mucosa to carcinoma proceeds through several stages that are associated withthe accumulation of genetic mutations. Evidence from epidemiologic and experimental studies indicates that dietary factors can actat various stages of colorectal carcinogenesis.

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43. Hoff G, Vatn MH, Larsen S. Relationship between tobaccosmoking and colorectal polyps. Scand J Gastroenterol.1987;22:13–16.

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